N-methyl-n&#39;-(2-amino ethyl sulfonyl)-piperazine

ABSTRACT

AMINOETHANESULFONYL DERIVATIVES HAVING A GENERAL FORMULA R-SO2CH2CH2Y WHERE R IS SELECTED FROM A GROUP CONSISTING OF THIAZOLYL-2-AMINO, 1-PYRROLYL, 4-METHYLPIPERAZYL, AND 1-INODOLYL AND Y IS NH2 OR, WHEN R IS THIAZOLYL-2-AMINO, SAID Y MAY BE NICOTINOYLAMINO AS WELL AS MANUFACTURE METHODS THEREOF WERE DISCLOSED.

United States Patent 3,836,535 N-METHYL-N'-(2-AMINO ETHYL SULFONYL)-PIPERAZINE Shun-Ichi Naito, 35 Murasakino Kamitoridacho, Kita-ku, Kyoto, Japan No Drawing. Original application July 19, 1971, Ser. No. 164,007, now Patent No. 3,743,647, dated July 3, 1973. Divided and this application Dec. 1, 1972, Ser. No. 311,252

Claims priority, application Japan, Aug. 27, 1970, 45/75,350, 45/75,351, 45/75,352; Dec. 18, 1970, 45/114,446, 45/114,447

Int. Cl. C07d 51/72 US. Cl. 260-268 S 2 Claims ABSTRACT OF THE DISCLOSURE Aminoethanesulfonyl derivatives having a general formula RSO CH CH Y where R is selected from a group consisting of thiazolyl-Z-amino, l-pyrrolyl, 4-methylpiperazyl, and l-indolyl and Y is NH or, when R is thiazolyl-Z-amino, said Y may be nicotinoylamino as well as manufacture methods thereof were disclosed.

This is a division of application Ser. No. 164,007 filed July 19, 1971, now Pat. No. 3,743,647 issued July 3, 1973.

The present invention relates to aminoethanesulfonyl derivatives of the general formula in which R is selected from a group consisting of S (thiazolyl-Z-amlno) If 1 N -pv o v (-methylpiperazyl) CHsN and (l-lndolyl) and Y is NH In case R is thiazolyl-Z-amino, the Y may also be nicotinoylamino. This invention also relates to manufacturing methods for these aminoethanesulfonyl derivatives.

All of these aminoethanesulfonyl derivatives are novel compounds having never been disclosed in any literature including patent specification. They are useful as medicines, such as analgesics, with little side effects. These compounds are characterized by containing taurine which is one of amino acids and has surface activity as well as analgesic action and, when they are given to human beings, their effects are not lowered even when subjected to a detoxication reaction in vivo such as an acetylation. Furthermore, some of these compounds are also useful as anti-histaminic, hypochloesterolemic and anti-inflammatory drugs.

Although the compounds of this invention have considerable water solubility, they are resistant to moisture to such an extent that, even when they are allowed to stand in an open container placed in a room for one year, more than of the content remains unchanged in most cases indicating little absorption of moisture. In addition, the aqueous solution thereof is also stable. Thus, for example, when a 5% aqueous solution of them is allowed to stand at room temperature for one year, more than 9095% thereof remains unchanged. This is practically advantageous, particularly in view of use of the compounds in injection.

Compounds of this invention can be manufactured by various routes which will be explained in detail.

Thus, for example, compounds where Y is nicotinoylamino group can be manufactured by nicotinoylation of the corresponding amino compounds or by nicotinoyl amination of the corresponding halides. The latter method (nicotinoylamination of halides) will be disclosed later' in an item of amination reaction.

The former method, i.e. nicotinoylation of aminoethanesulfonylaminothiazole (I), may be represented as:

m-Nus olcmomNn,

In order to carry out the present nicotinoylation, any of known method for nicotinoylation may be employed. It is preferred to effect the nicotinolylation by use of acids bearing a nicotinoyl group or the functional derivatives thereof such as acid anhydrides, acid esters, acid halides or the mixtures thereof. These acids and their functional derivatives may also be employed in the form of their salts. The reaction may be carried out at either normal temperature or with heating and under normal pressures or pressures above normal, depending upon the kinds, quantities or the like of the reactants used. Furthermore the starting material (I) of the present reaction may be employed in its salt form.

The present method will be further explained in detail with particular reference to the following examples, but it will be understood that these examples be preferred embodiments of the present method used only to illustrate but not limit the invention.

EXAMPLE 1 Into 0.1 mole of the starting material or its hydrochloride is added from to 200 ml. of anhydrous pyridine with subsequent addition of nicotinic acid chloride hydrochloride (0.1 mole). After heating the mixture for an hour, or, alternatively, standing the same whole day at a room temperature, the mixture is heated for an additional one hour. The pyridine is distilled olf under reduced pressure from the reaction mixture, the residue recrystallized several times from either methanol or from ethanol to obtain the desired product (II) as its hydrochloride having a melting point of 289 C. (Colorless needles). Into said residue from which the pyridine has been distilled off is added water and the mixture is made alkaline (pH about 9) by use of aqueous ammonia (of about 28%). The resulting mixture is evaporated under reduced pressure to dryness and the residue recrystallized several times from water to obtain the desired product (II) as colorless needles having a melting point of 228 C. The yields of the desired product and its hydrochloride are almost identical and within the range of from about 70 to 75% of the theory.

Element Analysis Desired product (II).Calculated for C H N O S C, 42.31; H, 3.85; N, 17.95. Found: C, 42.37; H, 3.90; N, 18.03.

The hydrochloride of the desired product (II).-- Calculated for C H N O S Cl C, 34.29; H, 3.64; N, 14.55. Found: C, 34.40; H, 3.51; N, 14.58.

Employment of nicotinic acid chloride in place of the nicotinic acid chloride hydrochloride did not cause any change in yields. Furthermore, it has been ascertained that the condensation reaction between the starting material (II) or the salt thereof, and nicotinic acid chloride can proceed also in water or various organic solvents, as well as in pyridine and that it also proceeds advantageously when a small quantity of pyridine or alkali is added into the water or various organic solvents.

For example, 0.1 mole of the starting material (I) or its hydrochloride is charged with 500 m1. of ethyl acetate, into which mixture 0.1 mole of nicotinic acid chloride hydrochloride is added followed by heating under reflux in water bath for 3 hours. After distilling olf the ethyl acetate from the reaction mixture remains yellowish solids, which are then recrystallized from ethanol or methanol to obtain the hydrochloride of the desired product (11). Alternatively, said residual solids are dissolved in a small amount of water, which solution is made alkaline by use of ammonia (pH about 9) and distilled under reduced pressure to remove the water. The: residue is recrystallized from water to obtain the desired product (H) in its pure form. In this case, the yield was little different from that obtained in the case of employment of pyridine as solvent.

In addition, in the following examples 2 and 3 are shown the embodiments of the invention wherein nicotinic acid anhydride and nicotinic acid are employed in place of nicotinic acid chloride(hydrochloride) used in Example 1..

EXAMPLE 2 Into a 100 ml. three-necked flask are placed 0.1 mole of the starting material (I), 0.1 mole of nicotinic acid anhydride and 100 ml. of anhydrous pyridine followed by heating the mixture on boiling water bath with agitation for 7 hours. The pyridine is distilled oil? under reduced pressure and to the residue is added strong aqueous ammonia (of about 28%) to make it alkaline, whereupon yellowish-white substance precipitates. The mixture is, as such, subjected to distillation under reduced pressure to remove the water, the residue recrystallized several times from water to obtain the desired product (II) in its pure form. The crystals, when subjected to mixed examination using the corresponding standard, show no lowering in their melting point. The yield is about 70%.

EXAMPLE 3 Into a three-necked flask with a water-separating tube attached thereto are charged 0.1 mole of the starting materials (I), 0.1 mole of nicotinic acid and 400 ml. of pcymene followed by heating with stirring at a temperature of from to C. for about 6 hours. The water formed is azeotropically distilled off. After cooling, the p-cymene is distilled off under reduced pressure, the residue being made alkaline (pH about 9) by use of strong aqueous ammonia followed by distilling off the water under reduced pressure. The residue is recrystallized several times from water to obtain the pure desired product (II). The product, when subjected to mixed examination using the corresponding standard material, show no lowering in its melting point. The yield is about 65%.

Referring now by way of precaution, the method according to the present invention can also be elfected by proceeding the reaction in the presence of catalyst. Nicotinoylaminoethane-sulfonylaminothiazol (II) contains, in its structure, a pyridine ring of nicotinic acid and, since the nitrogen atom in said ring is basic, it may be, of course, optionally reacted with any organic or inorganic acid to form the corresponding acid addition salt. Subsequently, in order to purify the end product, there may be employed, as well as the hydrochloride, any organic salts as for example, its fumarate, fiavianate or tartarate. For example, the end product (II) may be readily purified by forming its hydrochloride by either adding thereto concentrated hydrochloric acid followed by evaporation under reduced pressure to dryness or introducing gaseous HCl into a solution of the desired product (11) in methanol or ethanol, with subsequent recrystallization of the hydrochloride from methanol or ethanol.

The above disclosure is an explanation in detail of a method to manufacture nicotinoylamino compounds by nicotinoylation of the corresponding amino compounds.

Compounds of the present invention in which Y is an amino radical can be manufactured by the following two methods:

(1) Amination of the corresponding halides (2) Deacylation of the corresponding acylamino (or acylimino) compounds The amination according to (1) will be explained at first together with a nicotinoylamination of the corresponding halides for the sake of convenience.

Said amination method can be accomplished by the reaction of the halide of the formula R-SO CH CH Z (III) (where R is as defined already; Z is halogen) with ammonia or nicotinic acid amide.

The halogen designated by Z in the above-described formula is preferably chlorine, bromine or iodine, of which chlorine is particularly preferred.

The ammonia or nicotinic acid amide to be reacted may be used as such or after dissolving or suspending in water and/or organic solvent, and its salts with acids may also be employed, if desired. The reaction in accordance with the present invention may proceed under normal pressure, although it is preferred to carry out the reaction under pressure above normal, in which case it 1s more preferred to effect the reaction in the presence of catalyst as for example, NaI, C11 Cl NH I or the like compound.

The halides to be employed as the starting materials according to the present invention are also novel compounds having been described in no literature and may be prepared, for example, by reacting 2-aminothiazole, N- methylpiperazine, pyrrole or indole with haloethylsulfonyl halide.

The present invention will be further described in detail with particular reference to the following examples, but it will be understood that these examples be preferred embodiments of the present invention and the invention he never limited thereto.

EXAMPLE 4 Y=NH,

g. of the compound of the formula (III) wherein X is C1 is reacted in an autoclave in the presence of catalyst with either anhydrous ammonia or with ammonium carbonate and aqueous ammonia by heating the reactants. After completion of the reaction, the contents are made acidic by use of hydrochloric acid, the resulting precipitates removed by filtering off the same under suction, the filtrate evaporated under reduced pressure to dryness and the residue recrystallized from quantities of ethanol to obtain the hydrochloride of the desired product. Alternatively, the said filtrate is made alkaline by use of strong aqueous ammonia (to pH about 9) followed by evaporation under reduced pressure to dryness, the residue recrystallized from either water or from a mixture of water and acetone to obtain the desired product. The melting points and details of the reaction conditions are shown in Table 2, while the element analysis in Table 3.

perature of 100 C. for about 6 hours. The contents are thereafter made acidic by use of hydrochloric acid, the precipitates formed thereby filtered 01f under suction. The filtrate is evaporated under reduced pressure to dryness, the residue recrystallized from methanol or ethanol to obtain the hydrochloride of the desired product (i.e. nicotinoylaminoethanesulfonylaminothiazole hydrochloride).

Alternatively, the filtrate as described above is made alkaline by use of ammonia and evaporated under reduced pressure to dryness, the residue being recrystallized from water to obtain the desired product as colorless needles. Yield about Its molecular weight and element analysis are shown in Table 3. As in Example 4, there resulted some reduction in yield when there was employed, as the starting material, the bromide (Z=Br) or iodide (Z=I) or no catalysts were employed.

The desired product wherein R is thiazolyl-Z-amino and Y is nicotinoylamino has a melting point of 229 C. and the hydrochloride thereof of 288 C.

TABLE 3 Percent Calculated Found Molecular Compound formulas C H N C H N Ia N-methylplperazlne family" C7H11N3Q2S 40. 58 8.21 20.29 40.65 8.18 20.20 Ia (hydrochloride) N-methylplperazlne iamlly. C1H2oNa0zSClz 26. 50 6.31 13.25 26.72 6.28 13.33 11, Pyrrole family CeHmNzOzS 41.38 5.74 16.09 41.25 5.82 16.21 Ib (hydrochloride) d0 CeHrzNzOzSClz 29.15 4.87 11.34 29.28 4.76 11.42 Thiazole iamily u 12N40a$2 42.31 3.85 17. 95 42. as 3.91 17.72 In (hydrochloride) ...-.do CHHMN403SZC12 34. 29 3.64 14.55 34.31 3.60 14.47 Id do csHoNaozsz 28.99 4.35 20.29 29.12 4.21 20.34 Id (hydrochloride) do CIsHnNaOzSzCM 21.43 3.93 15.00 21.38 3.99 15. 23 1e Indolyl family CtoHrzNzOzS 53.57 5.36 12.50 53.63 5.28 12. e3 Ie (hydrochloride) CioHnNzOzSCl 46.07 4.99 10.75 46.11 4.89 10.68

TABLE 1 The above is an explanation as to the manufacture of of the the desired compounds by amination (and nicotinoylam- M.P. of hydrochloination) of the corresponding halides. ,2 3 25,323 As hereunder is an explanation of deacylation of the product, product, corresponding acylamino (or acylimino) compounds. R degrees degrees More particularly, said method is concerned with a process 1345-352 31 -319 for preparing the desired products by deacylating, by way of hydrolysis or hydrazinolysis, a compound represented 1 by the general formula 1 352-356 1 319-322 R-SO CH CH Q (II) wherein R represents the same meanings as described (Ib) above and Q is an acylamino or acylimino group. Pre- 325 332 2216 5 ferred examples of the acylamino group include aliphatic H I acylamino groups such as acetylamino and propionylamino groups, as well as aromatic amino groups such as benzoylammo and nicotinoylamino groups. Preferred example of (Id) the acylammo group is phthalimino group. Of course, 8323428 8258464 these specific examples of the acylamino and acylimino groups are meutloned only by way of example to explam the present invention. Therefore it will be understood that the present invention be by no means restricted to employment of such specific examples. (1e) The above-described hydrolysis may be effected ad- 1 Colored and decomposedfiolofless crystals vantageously 1n any known manner where there are ema Colorless cry5t ployed, for example, acids, sodium alcoholate, alkali metal Colored and dewmposedhydroxides, alkali metal carbonates or the like materials. TABLE 2 In particular, preferred results may be obtained in the Yield Cataryst and present mventlon when a concentrated solution of alkali stmm Reatit lgg Tempm (p c gg fii metal hydroxide such as NaOI-I or KOH. amine (hrs.) ture C.) Ia In m t thereof (g When the deacylation of the invention is to be effected ydmus by hydrazinolysls, there may be employed any known m om (20) 5 100 50 43 36 3 8 8 3 rniedthgd for it, such as one wherein hydrazine hydrate is 0 5 100 52 45 40 4 n2 2 a e into a methanolic or ethanolic solution with sub- 1 NBCOQ (10) 8 140 38 34 30 38 4) sequent treatment with hydrochloric acrd.

l 28% NHlOH (20 1:01.).

EXAMPLE 5 (Y-=Nicotinoylamino) (c) To 5 g. of the compound of the formula (II) wherein R is thiazolyl and Z is Cl is added 8 g. of nicotinic acid amide or its hydrochloride, and the mixture is reacted, in an autoclave, in the presence of 3 g. of Cu cl at a tem- Starting materials in this method are also novel com pounds having never been described in any literature and may be prepared, for example, by the reaction of N-methylpiperazine, pyrrole, indole or 2-aminothiazo1e with an acylaminoethanesulfonyl halide.

The present method will be further illustrated in detail with particular reference to the following examples, but it will be understood that these examples be preferred embodiments of the present method and the present invention be never limited thereto.

Into the starting material wherein Q is phthalimino group is added a 30 w./v. percent solution of hydroxide "8 All of the resulting products are in the form of colorless crystals.

followed by boiling the mixture under reflux for 3-5 hours. L 5 After cooling the mixture is made acidic by use of con- 5 Amount centrated hydrochloric acid while ice-cooling, and then R Q 5;? i i adjusted to a pH of about 9 by addition of sodium carbonate. The crystals precipitated thereby are separately Phtha H 1 stored. The filtrate is evaporated under reduced pressure 3 N N Aetamlm 0 f 7 to dryness, the residue being recrystallized from either 10 Y h h 1o water or from a mixture of water and acetone and the fi i fif e 10 :13 resulting crystals, together with the previously stored t crystals, being recrystallized several times from either phthalqnino 10 water or from a mixture of water and acetone to obtain Acetammo 6.2 the desired product as colorless crystals. The details of 15 i these reactions are shown in Table 4. N/

Similar procedures are repeated except that there are employed, as the starting material, ones wherein Q is ben- 'Phthalimino m 3 2 zoylamino or acetylarnino group, the corresponding de- Aeetamin0 10 3:5 sired products are obtained in yields as tabulated in Table lL 5. The element analysis of the desired products thus obs tained are shown in Table 6.

TABLE 6 Percent Calculated Found Molecular R formula C H N C H N CH NOS 40.58 3.21 20.29 40.67 8.18 2. H3G N 1 11 a z 033 CBHXONQOZS 41.38 5.74 16.09 41.25 5.33 16.22

CXOHXZNZOZS 53.27 5.36 12.50 53.68 5.38 12.60

-|N CtsHoNAOzSz 28.99 4.35 20. 29 29. 05 4.30 20.38 \SLNHF.

TABLE 4 EXAMPLE 6 Amount M.P. of To the starting material wherein Q is phthalimino group g ggggg ,223 is added from about 5 to 8 times its volume of 95% solution product, Yield, ethanol followed by the addition of 1.1 times its molar R 10 added (1111.) degrees amount of hydrazine hydrate (of about 100%). The mix- 50 345,352 3.2 ture is heated under reflux for about 2 hours with con- HaC-N tinuous stirring. Thereafter, the mixture is adjusted to a pH of about 1 by the addition of hydrochloric acid, heated 50 352-356 on water bath for further about 30 minutes and filtered in hot to remove the precipitated phthalic acid 40 323L330 8. 5 hydrazide, the filtrate being cooled to precipitate the hydrochloride of the desired product which is then fiitered and then recrystallized several times to purify the same. [Alternatively, the said filtrate is evaporated under reduced pressure to dryness and the residue is made alkaline (pH about 9) by the addition of a Na CO solution fol- N 40 325-332 2.3

lowed by evaporating again under reduced pressure to dryness. The residue is recrystallized several times from water or from a mixture of water and acetone to obtain the free desired product] The details of the reactions are shown in Table 7. In addition, the element analysis of the hydrochloride of the desired product is shown in 2. The compound according to claim 1 which has the Table 8. formula:

By the way, when, in Example 6, sodium carbonate is employed to make the reaction mixture alkaline, the hydrochloride as obtained in this example may be also ob- CHa-N N-SOzCHzCHaNHg tained by reducing the amount thereof added and thereby 5 making the mixture weakly acidic.

TABLE 7 Amount M.P. of the Solvent; of the Amount of HCl salt of used for starting hydrazine the desired recrystalmaterial hydrate product, Yiel linin the R used (g.) (g.) degree (g.) HCl salt 130 22 318-319 52 Ethanol. CH3N N- \N 122 22 1 319-322 45 Do.

Ffii 325-332 Methanol.

1 Colored and decomposed.

TABLE 8 Percent Calculated Found R Molecular formula C H N C H N CrHzoNaOzSCl 26.50 6.31 13. 25 26. 43 6. 45 13.38 CH3N N- \N CBH12N202SC1 29. 51 4. 87 11. 34 29.27 4. 78 11.45

CroHnNzOzSCl 46.07 4.99 10.75 46. 11 4.87 10. 82

l We claim: No references cited.

1. A compound of the formula:

DONALD G. DAUS, Primary Examiner CHCI N NSO;CH;CH;NH J. TOVAR, Assistant Examiner and the pharmaceutically acceptable acid addition salts thereof. 260294.8 D, 294.8 F, 306.8 R, 326.12 R; 424-250 

